Cancer is a serious hazard to human life and health. With the changes of external factors such as environmental pollution, the number of cancer cases is rising year by year. Therefore, the study on the cancer mechanisms and the treatment methods of cancer is becoming more and more extensive.
In recent years, with the rapid development of tumor biology and related disciplines, some basic processes of cell carcinogenesis are gradually established, such as signal transduction in malignant tumor cell and cell apoptosis induction. The development of antitumor drugs has been gradually changed from interfering cell growth cycle to attacking the related enzymes of tumor cells, such as the epidermal growth factor and vascular endothelial growth factor, which makes the treatment of tumor change from the cellular level to the molecular level and produce many molecular-targeted drugs. On the basis of differences between normal cells and tumor cells, the new tumor target drugs can selectively act on tumor cell specific kinase of proliferation differentiation and have the advantages of high efficiency, low toxicity and strong specificity. So the research of kinase-targeted drugs has become the important direction.
Among the kinases as drug targets, protein kinases are the most deeply developed ones. The mutations and rearrangements of protein kinases lead to preventions or disorders in the process of signal transduction as first, and the cell disorder of growth, differentiation and proliferation subsequently and multitude tumors eventually.
Protein kinases (PKs), including protein tyrosine kinase (PTK) and serine-threonine kinase (STK), catalyze the phosphorylation of hydroxyl group on tyrosine, serine and threonine residues through the transfer of the end of ATP phosphate. Through signal transduction pathways, these enzymes regulate cell growth, differentiation and proliferation. By combining with growth factor ligand, the growth factor receptor PTK turns into an activated form, which interacts with the protein on the inner surface of cell membrane. It leads to the phosphorylation of the residues on receptors and other protein tyrosines, and the formation of multiple cytoplasmic signaling molecule complexes, which affect cell reaction, such as division (proliferation), differentiation, growth, metabolism and so on.
Growth factor receptors with PTK activity are called receptor tyrosine kinases (RTKs), which includes a big family of transmembrane receptors with multiple biological activities. c-Met is one of the members of Ron subfamily of RTK family, which is the only known high affinity receptor of hepatocyte growth factor (HGF). Human c-Met gene is located on the 7th chromosome (7q31), about 110 kb, included 21 exons. The mature c-Met is a heterodimeric which is composed of 5.0×104 α- and 1.4×105 β-subunits. α-Subunit is located in the extracellular, and β-subunit includes extracellular region, transmembrane region and intracellular region. Extracellular regions of α- and β-subunits are combined with HGF and act as the ligand recognition site. Whereas, the intracellular region possesses tyrosine kinase activity, which is the interacting parts of many signaling molecules. HGF/c-Met signaling pathways exist widely in all kinds of cells and play an essential role of physiological regulation during many tissues and organs of growth and development. But the overexpression of HGF or c-Met in cells lead to the invasion and metastasis of tumor cells. (Israel Cañadas, Federico Rojo, Montserrat Arumí-Uría, et al. Clin Transl Oncol. 2010, 12: 253-260)
As a kind of oncogene, the overexpression or down regulation of c-Met lead to tumor growth and invasion. Therefore, the expression of c-Met is considered to play a role in the early stage of tumor cell growth and migration. Stimulated by ligand HGF, c-Met starts a variety of physiological processes containing cell proliferation, motility, differentiation, angiogenesis, wound healing, tissue regeneration, embryonic development. Therefore, c-Met plays an important role in the enhancement of tumor cell growth, the modulation tumor cell metastasis, the advancement tumor cell invasion and the angiogenesis of tumor. For this reason, c-Met becomes an important target for the development of anticancer drug (Xiangdong Liu, Robert C. Newton, Peggy A. Scherle. Trends in Molecular Medicine. 2009, 16(1): 37-45).
Foretinib (GSK1363089, XL880), an quinoline derivative, is an oral c-Met and VEGFR/KDR kinase inhibitor with IC50 values of 0.4 and 0.8 nM to c-Met and KDR, respectively. It has entered phase II clinical trial (WO2010036831A1). Foretinib has shown significant inhibitory effects against a variety of human tumor cell lines (such as human lung cancer cells, human gastric cancer cells, etc.), with an IC50 values of about 0.004 mg/mL.

Basing on the reported literatures, the inventor designed and synthesized a new serial of quinoline derivatives, which possessed potent antitumor activity in vitro.